TolerGen, Inc. is an entrepreneurial biotechnology company established in 1997 devoted to the development and commercialization of novel therapies for inducing and maintaining epitope-specific immune tolerance using genetic engineering strategies. Based on the hypothesis that self immunoglobulins and B-cell antigen presentation would be highly tolerogenic, we have engineered retroviral constructs containing multiple epitopes in frame at the N-terminus of a murine IgG1 H chain. Recipients of bone marrow or peripheral B cells transduced with these vectors are tolerant to the expressed genes. Data in two experimental autoimmune models (uveitis and EAE) are promising in that significant clinical efficacy has been achieved. It is not clear, however, what the practical limits are for the antigenic epitopes employed in this platform and the best vectors to deliver our gene therapy for tolerance. Since the acetylcholine receptor (AChR) is a major target for the immune response in the autoimmune disease, myasthenia gravis, we plan to synthesize a series of overlapping 100-mers of the alpha subunit of the AChR and full length AChR on the IgG scaffold. Our first goal is to determine whether these antigens can be effectively presented by transduced LPS blasts to induce tolerance to multiple AChR epitopes in our gene therapy model. Next, we will apply these to an FIV-based non-primate lentivirus vectors for expression and eventual tolerance induction as an important step toward future clinical trials in humans. The accomplishment of these two aims will enable us to design a specific product, an AChR or multimeric epitope-linked Ig vector, that can be used therapeutically to modulate autoimmunity in myasthenia gravis. Our approaches will allow us to predict that tolerance to larger molecules can be achieved via this technique and that the host can then present the relevant epitopes in a haplotype-specific manner for tolerance induction in autoimmune diseases, as well as for proteins of gene therapeutic interest. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE